Tumor mutational burden is site specific in non–small-cell lung cancer and is highest in lung adenocarcinoma brain metastases

PURPOSE Tumor mutational burden (TMB) is a developing biomarker in non–small-cell lung cancer (NSCLC). Little is known regarding differences between TMB and sample location, histology, or other biomarkers. METHODS A total of 3,424 unmatched NSCLC samples, including 2,351 lung adenocarcinomas (LUADs) and 1,073 lung squamous cell carcinomas (LUSCs), underwent profiling, including next-generation sequencing of 592 cancer-related genes, programmed death ligand 1 immunohistochemistry, and TMB. The rate TMB of 10 mutations per megabase (Mb) or greater was compared between primary and metastatic LUAD and LUSC. Molecular alteration frequency was compared at a cutoff of 10 mutations/Mb. RESULTS LUAD metastases were more likely to have a TMB of 10 mutations/Mb or greater compared with primary LUADs (38% v 25%; P, .001), and this difference was most pronounced with brain metastases (61% v 35% for other metastases; P, .001). The median TMB for LUAD brain metastases was 13 mutations/Mb compared with six mutations/Mb for primary LUADs. Variability existed for other LUAD metastasis sites, with adrenal metastases most likely to meet the cutoff of 10 mutations/Mb (51%) and bone metastases least likely to meet the cutoff (19%). TMB was more commonly 10 mutations/Mb or greater for LUSC primary tumors than for LUAD primary tumors (35% v 25%, respectively; P, .001). LUSC metastases were more likely to have a TMB of 10 mutations/Mb or greater than LUSC primary tumors. Poorly differentiated disease was more likely have a TMB of 10 mutations/Mb or greater when stratified by histology and primary tumor or metastasis. Site-specific molecular differences existed at this TMB cutoff including programmed death ligand 1 positivity and STK11 and KRAS mutation rate. CONCLUSION TMB is a site-specific biomarker in NSCLC with important spatial and histologic differences. TMB is more frequently 10 mutations/Mb or greater in LUAD and LUSC metastases and highest in LUAD brain metastases. Along this TMB cutoff, clinically informative distinctions exist in other tumor profiling characteristics. Further investigation is needed to expand on these findings.